Evidence-Based Reviews

Cannabinoid-based medications for pain

Current Psychiatry. 2021 May;20(5):21-23,28-33 | doi:10.12788/cp.0121

References

1. Okie S. A floor of opioids, a rising tide of deaths. N Engl J Med. 2010;363(21):1981-1985. doi:10.1056/NEJMp1011512
2. Powell D, Pacula RL, Taylor E. How increasing medical access to opioids contributes to the opioid epidemic: evidence from Medicare Part D. J Health Econ. 2020;71:102286. doi: 10.1016/j.jhealeco.2019.102286
3. Manzanares J, Julian MD, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257. doi: 10.2174/157015906778019527
4. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833. doi: 10.3390/ijms19030833
5. Huang WJ, Chen WW, Zhang X. Endocannabinoid system: role in depression, reward and pain control (Review). Mol Med Rep. 2016;14(4):2899-2903. doi:10.3892/mmr.2016.5585
6. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83-90. doi:10.1016/0006-2952(95)00109-d
7. Walker JM, Krey JF, Chu CJ, et al. Endocannabinoids and related fatty acid derivatives in pain modulation. Chem Phys Lipids. 2002;121(1-2):159-172. doi: 10.1016/s0009-3084(02)00152-4
8. Howlett AC. Efficacy in CB1 receptor-mediated signal transduction. Br J Pharmacol. 2004;142(8):1209-1218. doi: 10.1038/sj.bjp.0705881
9. Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid inactivation, biochemistry and pharmacology. J Pharmacol Exp Ther. 2001;298:7-14.
10. Piomelli D, Beltramo M, Giuffrida A, et al. Endogenous cannabinoid signaling. Neurobiol Dis. 1998;5(6 Pt B):462-473. doi: 10.1006/nbdi.1998.0221
11. Eggan SM, Lewis DA. Immunocytochemical distribution of the cannabinoid CB1 receptor in the primate neocortex: a regional and laminar analysis. Cereb Cortex. 2007;17(1):175-191. doi: 10.1093/cercor/bhj136
12. Jennings EA, Vaughan CW, Christie MJ. Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J Physiol. 2001;534(Pt 3):805-812. doi: 10.1111/j.1469-7793.2001.00805.x
13. Vaughan CW, Connor M, Bagley EE, et al. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol. 2000;57(2):288-295.
14. Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol. 1999;127(4):935-940. doi: 10.1038/sj.bjp.0702636
15. Raichlen DA, Foster AD, Gerdeman GI, et al. Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the “runner’s high.” J Exp Biol. 2012;215(Pt 8):1331-1336. doi: 10.1242/jeb.063677
16. Beltrano M. Cannabinoid type 2 receptor as a target for chronic pain. Mini Rev Chem. 2009;234:253-254.
17. Ibrahim MM, Deng H, Zvonok A, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100(18):10529-10533. doi: 10.1073/pnas.1834309100
18. Valenzano KJ, Tafessem L, Lee G, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005;48:658-672.
19. Pertwee RG, Howlett AC, Abood ME, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62(4):588-631. doi: 10.1124/pr.110.003004
20. Carter GT, Weydt P, Kyashna-Tocha M, et al. Medicinal cannabis: rational guidelines for dosing. Drugs. 2004;7(5):464-470.
21. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770-1804.
22. Johal H, Devji T, Chang Y, et al. cannabinoids in chronic non-cancer pain: a systematic review and meta-analysis. Clin Med Insights Arthritis Musculoskelet Disord. 2020;13:1179544120906461. doi: 10.1177/1179544120906461
23. Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). Am J Bot. 2004;91(6):966-975. doi: 10.3732/ajb.91.6.966
24. Hazekamp A, Ware MA, Muller-Vahl KR, et al. The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms. J Psychoactive Drugs. 2013;45(3):199-210. doi: 10.1080/02791072.2013.805976
25. Andreae MH, Carter GM, Shaparin N, et al. inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain. 2015;16(12):1221-1232. doi: 10.1016/j.jpain.2015.07.009
26. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473. doi: 10.1001/jama.2015.6358
27. Boychuk DG, Goddard G, Mauro G, et al. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015;29(1):7-14. doi: 10.11607/ofph.1274
28. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol. 2011;72(5):735-744. doi: 10.1111/j.1365-2125.2011.03970.x
29. Stockings E, Campbell G, Hall WD, et al. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain. 2018;159(10):1932-1954. doi: 10.1097/j.pain.0000000000001293
30. Mücke M, Phillips T, Radbruch L, et al. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3(3):CD012182. doi: 10.1002/14651858.CD012182.pub2
31. Häuser W, Fitzcharles MA, Radbruch L, et al. Cannabinoids in pain management and palliative medicine. Dtsch Arztebl Int. 2017;114(38):627-634. doi: 10.3238/arztebl.2017.0627
32. Dworkin RH, Turk DC, Wyrwich KW, et al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008;9(2):105-121. doi: 10.1016/j.jpain.2007.09.005
33. Farrar JT, Troxel AB, Stott C, et al. Validity, reliability, and clinical importance of change in a 0-10 numeric rating scale measure of spasticity: a post hoc analysis of a randomized, double-blind, placebo-controlled trial. Clin Ther. 2008;30(5):974-985. doi: 10.1016/j.clinthera.2008.05.011
34. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-335. doi: 10.1155/2014/754693
35. Petzke F, Enax-Krumova EK, Häuser W. Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: a systematic review of randomized controlled studies. Schmerz. 2016;30(1):62-88. doi: 10.1007/s00482-015-0089-y
36. Rice J, Cameron M. Cannabinoids for treatment of MS symptoms: state of the evidence. Curr Neurol Neurosci Rep. 2018;18(8):50. doi: 10.1007/s11910-018-0859-x
37. Koppel BS, Brust JCM, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders. Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(17):1556-1563. doi: 10.1212/WNL.0000000000000363
38. Kafil TS, Nguyen TM, MacDonald JK, et al. Cannabis for the treatment of Crohn’s disease and ulcerative colitis: evidence from Cochrane Reviews. Inflamm Bowel Dis. 2020;26(4):502-509. doi: 10.1093/ibd/izz233
39. Katz-Talmor D, Katz I, Porat-Katz BS, et al. Cannabinoids for the treatment of rheumatic diseases - where do we stand? Nat Rev Rheumatol. 2018;14(8):488-498. doi: 10.1038/s41584-018-0025-5
40. Walitt B, Klose P, Fitzcharles MA, et al. Cannabinoids for fibromyalgia. Cochrane Database Syst Rev. 2016;7(7):CD011694. doi: 10.1002/14651858.CD011694.pub2
41. Bar-Lev Schleider L, Mechoulam R, Lederman V, et al. Prospective analysis of safety and efficacy of medical cannabis in large unselected population of patients with cancer. Eur J Intern Med. 2018;49:37‐43. doi: 10.1016/j.ejim.2018.01.023
42. Bennett M, Paice JA, Wallace M. Pain and opioids in cancer care: benefits, risks, and alternatives. Am Soc Clin Oncol Educ Book. 2017;37:705‐713. doi:10.1200/EDBK_180469
43. Blake A, Wan BA, Malek L, et al. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017;6(Suppl 2):5215-5222. doi: 10.21037/apm.2017.08.05
44. Aviram J, Samuelly-Lechtag G. Efficacy of cannabis-based medicines for pain management: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2017;20(6):E755-E796.
45. Häuser W, Welsch P, Klose P, et al. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain: a systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019;33(5):424-436. doi: 10.1007/s00482-019-0373-3
46. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manage 2010; 39:167-179.
47. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438-449. doi: 10.1016/j.jpain.2012.01.003
48. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage. 2014;47(1):166-173. doi: 10.1016/j.jpainsymman.2013.02.018
49. Kleckner AS, Kleckner IR, Kamen CS, et al. Opportunities for cannabis in supportive care in cancer. Ther Adv Med Oncol. 2019;11:1758835919866362. doi: 10.1177/1758835919866362
50. National Conference of State Legislatures (ncsl.org). State Medical Marijuana Laws. Accessed April 5, 2021. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
51. Hasin DS, Shmulewitz D, Cerda M, et al. US adults with pain, a group increasingly vulnerable to nonmedical cannabis use and cannabis use disorder: 2001-2002 and 2012-2013. Am J Psychiatry. 2020;177(7):611-618. doi: 10.1176/appi.ajp.2019.19030284
52. Hasin DS, Sarvet AL, Cerdá M, et al. US adult illicit cannabis use, cannabis use disorder, and medical marijuana laws: 1991-1992 to 2012-2013. JAMA Psychiatry. 2017;74(6):579-588. doi: 10.1001/jamapsychiatry.2017.0724
53. National Institute on Drug Abuse. Illicit cannabis use and use disorders increase in states with medical marijuana laws. April 26, 2017. Accessed October 24, 2020. https://archives.drugabuse.gov/news-events/news-releases/2017/04/illicit-cannabis-use-use-disorders-increase-in-states-medical-marijuana-laws
54. National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. The National Academies Press; 2017. https://doi.org/10.17226/24625
55. Stanford M. Physician recommended marijuana: contraindications & standards of care. A review of the literature. Accessed July 7, 2020. http://drneurosci.com/MedicalMarijuanaStandardsofCare.pdf
56. Repp K, Raich A. Marijuana and health: a comprehensive review of 20 years of research. Washington County Oregon Department of Health and Human Services. 2014. Accessed April 8, 2021. https://www.co.washington.or.us/CAO/upload/HHSmarijuana-review.pdf
57. Parmar JR, Forrest BD, Freeman RA. Medical marijuana patient counseling points for health care professionals based on trends in the medical uses, efficacy, and adverse effects of cannabis-based pharmaceutical drugs. Res Social Adm Pharm. 2016;12(4):638-654. doi: 10.1016/j.sapharm.2015.09.002.
58. Leite RT, Nogueira Sde O, do Nascimento JP, et al. The use of cannabis as a predictor of early onset of bipolar disorder and suicide attempts. Neural Plast. 2015;2015:434127. doi: 10.1155/2015/43412
59. Kim SW, Dodd S, Berk L, et al. Impact of cannabis use on long-term remission in bipolar I and schizoaffective disorder. Psychiatry Investig. 2015;12(3):349-355. doi: 10.4306/pi.2015.12.3.349
60. Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis. Lancet Psychiatry. 2019;6(12):995-1010.
61. Wilkinson ST, Radhakrishnan R, D’Souza DC. A systematic review of the evidence for medical marijuana in psychiatric indications. J Clin Psychiatry. 2016;77(8):1050-1064. doi: 10.4088/JCP.15r10036.
62. Woolf CJ, American College of Physicians. American Physiological Society Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140(6):441-451.
63. Crippa JA, Zuardi AW, Martín-Santos R, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24(7):515‐523. doi: 10.1002/hup.1048
64. Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology of cannabinoids. Neurotherapeutics. 2015;12(4):735‐746. doi: 10.1007/s13311-015-0380-8
65. Antoniou T, Bodkin J, Ho JMW. Drug interactions with cannabinoids. CMAJ. 2020;2;192:E206. doi: 10.1503/cmaj.191097
66. Brown JD. Potential adverse drug events with tetrahydrocannabinol (THC) due to drug-drug interactions. J Clin Med. 2020;9(4):919. doi: 10.3390/jcm9040919.
67. Maida V, Daeninck P. A user’s guide to cannabinoid therapy in oncology. Curr Oncol. 2016;23(6):398-406. doi: http://dx.doi.org/10.3747/co.23.3487
68. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46(1):86-95. doi: 10.3109/03602532.2013.849268
69. Abrams DI. Integrating cannabis into clinical cancer care. Curr Oncol. 2016;23(52):S8-S14.
70. Alsherbiny MA, Li CG. Medicinal cannabis—potential drug interactions. Medicines. 2018;6(1):3. doi: 10.3390/medicines6010003
71. Lucas CJ, Galettis P, Schneider J. The pharmacokinetics and the pharmacodynamics of cannabinoids. Br J Clin Pharmacol. 2018;84:2477-2482.
72. Ghasemiesfe M, Barrow B, Leonard S, et al. Association between marijuana use and risk of cancer: a systematic review and meta-analysis. JAMA Netw Open. 2019;2(11):e1916318. doi: 10.1001/jamanetworkopen.2019.16318
73. Riggs PK, Vaida F, Rossi SS, et al. A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men. Brain Res. 2012;1431:46-52. doi: 10.1016/j.brainres.2011.11.001
74. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. BMJ. 2012;344:e536. doi: 10.1136/bmj.e536
75. Carlier J, Huestis MA, Zaami S, et al. Monitoring perinatal exposure to cannabis and synthetic cannabinoids. Ther Drug Monit. 2020;42(2):194-204.

Cannabinoid-based medications

Marijuana contains multiple components (cannabinoids). The most extensively studied are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Because it predominantly binds CB1 receptors centrally, THC is the major psychoactive component of cannabis; it promotes sleep and appetite, influences anxiety, and produces the “high” associated with cannabis use. By contrast, CBD weakly binds CB1 and thus exerts minimal or no psychoactive effects.¹⁹

Cannabinoid absorption, metabolism, bioavailability, and clinical effects vary depending on the formulation and method of administration (Table 1).^20-22 THC and CBD content and potency in inhaled cannabis can vary significantly depending on the strains of the cannabis plant and manner of cultivation.²³To standardize approaches for administering cannabinoids in clinical trials and for clinical use, researchers have developed pharmaceutical analogs that contain extracted chemicals or synthetic chemicals similar to THC and/or CBD.

In this article, CBM refers to smoked/vaporized herbal cannabis as well as pharmaceutical cannabis analogs. Table 2 summarizes the characteristics of CBM commonly used in studies investigating their use for managing pain conditions.

CBM for chronic pain

The literature base examining the role of CBM for managing chronic nonmalignant and malignant pain of varying etiologies is rapidly expanding. Randomized controlled trials (RCTs) have focused on inhaled/smoked products and related cannabinoid medications, some of which are FDA-approved (Table 2).

A multitude of other cannabinoid-based products are currently commercially available to consumers, including tincture and oil-based products; over-the-counter CBD products; and several other formulations of CBM (eg, edible and suppository products). Because such products are not standardized or quality-controlled,²⁴ RCTs have not assessed their efficacy for mitigating pain. Consequently, the findings summarized in this article do not address the utility of these agents.

Continue to: CBM for non-cancer pain

Cannabinoid-based medications for pain

References

Cannabinoid-based medications

CBM for chronic pain

Pages

Recommended Reading